HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Brown, R. J. P. Articles by Ball, J. K. Search for Related Content PubMed PubMed Citation Articles by Brown, R. J. P. Articles by Ball, J. K. Agricola Articles by Brown, R. J. P. Articles by Ball, J. K.

Cross-genotype characterization of genetic diversity and molecular adaptation in hepatitis C virus envelope glycoprotein genes

The University of Nottingham, Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, Division of Microbiology and Infectious Diseases, Queens Medical Centre, A Floor, West Block, Nottingham NG7 2UH, UK

Correspondence
Richard J. P. Brown
richard.brown{at}nottingham.ac.uk

Investigation of the mechanisms underlying hepatitis C virus (HCV) envelope glycoprotein gene evolution will greatly assist rational development of broadly neutralizing antibody-based vaccines or vaccine components. Previously, comprehensive cross-genotype evolutionary studies of E1E2 have not been possible due to the paucity of full-length envelope gene sequences representative of all major HCV genotypes (1–6) deposited in international sequence databases. To address this shortfall, a full-length E1E2 clone panel, corresponding to genotypes of HCV that were previously under-represented, was generated. This panel, coupled with divergent isolates available via international sequence databases, was subjected to high-resolution methods for determining codon-substitution patterns, enabling a fine-scale dissection of the selective pressures operating on HCV E1E2. Whilst no evidence for positive selection was observed in E1, the E2 protein contained a number of sites under strong positive selection. A high proportion of these sites were located within the first hypervariable region (HVR1), and statistical analysis revealed that cross-genotype adaptive mutations were restricted to a subset of homologous positions within this region. Importantly, downstream of HVR1, a differential genotype-specific distribution of adaptive mutations was observed, suggesting that subtly different evolutionary pressures shape present-day genotype diversity in E2 outside HVR1. Despite these observations, it is demonstrated that purifying selection due to functional constraint is the major evolutionary force acting on HCV E1E2. These findings are important in the context of neutralizing-antibody vaccine targeting, as well as in contributing to our understanding of E1E2 function.

The GenBank/EMBL/DDBJ accession numbers for the sequence data reported here are EF043079–EF043105.

This article has been cited by other articles:

				A. W. Tarr, A. M. Owsianka, D. Jayaraj, R. J. P. Brown, T. P. Hickling, W. L. Irving, A. H. Patel, and J. K. Ball Determination of the human antibody response to the epitope defined by the hepatitis C virus-neutralizing monoclonal antibody AP33 J. Gen. Virol., November 1, 2007; 88(11): 2991 - 3001. [Abstract] [Full Text] [PDF]

				P. Zhang, C. G. Wu, K. Mihalik, M. L. Virata-Theimer, M.-y. W. Yu, H. J. Alter, and S. M. Feinstone Hepatitis C virus epitope-specific neutralizing antibodies in Igs prepared from human plasma PNAS, May 15, 2007; 104(20): 8449 - 8454. [Abstract] [Full Text] [PDF]